Association between glutathione S-transferase gene M1 and T1 polymorphisms and chronic obstructive pulmonary disease risk: A meta-analysis

Chronic obstructive pulmonary disease (COPD) is a severe lung disease characterized by long-term breathing problems. A series of studies have indicated that the glutathione S-transferase genes M1 and T1 are associated with COPD susceptibility; however, the result still remains inconclusive. This meta-analysis was performed to estimate the effect of GSTM1 and GSTT1 polymorphisms in COPD risk. Eligible case-control studies published between January 2000 and December 2017 was searched and retrieved. A total of 37 articles were screened out, including 4674 COPD patients and 5006 controls. Overall, our results found that GSTM1 and GSTT1 null genotypes significantly increased the risk of COPD (GSTM1: odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.31-1.77, P <.00001; GSTT1: OR = 1.28, 95% CI = 1.09-1.50, P = .003). Subgroup analysis by ethnicity suggested that there was a close association between GSTM1 null polymorphism and COPD susceptibility in each studied ethnicity, while GSTT1 null polymorphism only showed association with Asian COPD patients. Moreover, we also found that joint GSTM1/GSTT1 null genotypes showed a high association with increased COPD susceptibility (OR = 1.42, 95% CI = 1.21-1.66, P < .0001). In conclusion, our results indicated that GSTM1 null, GSTT1 null, and the combined GSTM1/GSTT1 null genotypes might be risk factors in the development of COPD. However, future case-control studies with large-scale participants are still required to further estimate these associations.     

Polymorphisms of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis

Endometriosis, one of the most common gynaecologic disorders, shows significantly elevated prevalence in industrial areas and there is also a possible genetic predisposition. Glutathione-S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing carcinogens and mutagens that are present in human environments. An association between the incidence of endometriosis and the GST genotypes of patients has been suggested. The objective of the present study was to investigate whether the polymorphisms of GSTM1, GSTT1 and GSTP1 are related to endometriosis. Blood samples were available from 259 controls and 194 patients with advanced endometriosis diagnosed by both pathology and laparoscopic findings. The proportion of the GSTM1, GSTT1 and GSTP1 genotypes of the control group were comparable to other populations. There was no significant evidence that the distribution of the GSTM1 and GSTT1 genotype differed between the patients and the controls, with an allelic odds ratio (OR)=1.074 [95% confidence interval (CI)=0.737-1.564] and 1.239 (95% CI = 0.853-1.799), respectively. Also, there was no significant difference in the proportion of GSTP1 genotypes between the women with endometriosis and the control group with the OR = 0.823 (95% CI = 0.536-1.264). The higher risk alleles were contended as GSTM1, GSTT1 null mutation and GSTP1 Ile105Ile polymorphism. There was no significant increase in the risk of endometriosis as the number of higher risk alleles of the GST family increased. In conclusion, our findings suggest that the GSTM1, GSTT1 and GSTP1 genetic polymorphisms are not associated with the development of endometriosis in Korean women.     

Glutathione S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis of genetic association studies

In view of the controversies surrounding the glutathione S-transferases (GST) M1/T1-endometriosis association, a meta-analysis of the GSTM1/GSTT1 genetic association studies of endometriosis was performed. In this meta-analysis involving 14 GSTM1 studies with 1539 cases and 1805 controls and nine GSTT1 studies with 746 cases and 834 controls, respectively, substantial heterogeneities among studies were found. In addition, asymmetry in funnel plot was evident, which is likely to stem from publication bias, given no apparent indication of true heterogeneity. The bias appears to be prominent for GSTM1 studies, but is less so for GSTT1 studies. After correction for this bias, there is no evidence that women with GSTM1 null genotype have increased risk of developing endometriosis as compared with women with other genotypes. For GSTT1, the risk associated with the null genotype is 29% higher than other genotypes. However, even this estimate should be viewed with a large grain of salt, because the estimate could easily lose its statistical significance if there is a realistic 69-80% publication probability.     

Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population

Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. As the incidence of lung cancer is known to differ according to ethnicity, we have conducted a case-control study of 146 South Indian lung cancer patients along with 146 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of lung cancer in our population. The current weight of evidence from our study indicated that the frequency of CYP1A1 MspI homozygous variant alleles was significantly higher in cases (OR=3.178). We observed a considerable difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR=2.472, 95% CI: 1.191–5.094, P=0.014). There was no relative risk in GSTM1 null genotype when analysed singly (P=0.453). Considering genotype combinations, risk of lung cancer increased remarkably significantly in individuals having one variant allele of CYP1A1, GSTM1, or GSTT1, suggesting gene–gene interactions. Rare genotypic combinations (such as CYP1A1 wild GSTM1 or GSTT1 either null; CYP1A1 variant both GSTM1 and GSTT1 present; CYP1A1 variant GSTM1 or GSTT1 either null), were at higher risk compared to the reference group. Moreover, patients who had smoked <20 pack years and harboured the CYP1A1 variant allele or the GSTT1 null genotype also had a significant risk of lung cancer. Hence our study—the first to analyse a South Indian population—suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.     

Genetic Polymorphism of Glutathione S Transferases M1 and T1 in Indian Patients with Hepatocellular Carcinoma

Objective: Our aim was to evaluate whether the association of GSTM1/T1 gene polymorphisms modifies the risk of Hepatocellular carcinoma (HCC) and what is its correlation with other predisposing risk factors like alcohol intake, cigarette smoking and hepatitis B and C infections. Study design/setting: It was a case-control study, included 254 HCC cases compared with 525 hospital-based age and sex matched cases of chronic liver disease without HCC as controls from Indian population. The GSTM1 and GSTT1 genotypes were detected using conventional multiplex PCR method. Results: In this case-control study, we observed a positive correlation between age, HBV and HCV infection, smoking habit of > 20 packs/year, alcohol consumption of > 100 g/day and risk of liver cancer. We found significantly increased risk associated with GSTM1 null genotype (OR = 3.49; 95% CI = 2.52–4.84) as well as GSTT1 null genotype (OR = 3.12; 95% CI = 2.19–4.45), respectively. However, an increased risk of HCC was observed among heavy drinkers with GSTM1 (OR = 2.01; 95% CI = 1.11–3.66). Further, cigarette smoking showed a non-significant association with GSTT1 (OR = 1.49; CI = 0.69–3.25). Conclusion: Our results suggest that the variants in low penetrance gene such as GSTM1 and GSTT1 are associated with an increased liver cancer risk. Further, an influence of GSTM1/T1 null genotypes may contribute in the etiology of HCC in patients with higher cigarette and alcohol consumption.     

The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population

BACKGROUND: Susceptibility to bladder cancer is thought to depend on interplay between genetic factors and environmental chemical carcinogens. AIM: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population. METHOD: Sixty-two patients with transitional cell carcinoma of the bladder cancer and 79 controls were examined with respect to the frequency of GSTM1 and GSTT1 null genotypes. RESULTS: The frequencies of the GSTT1 null in the total group of bladder cancer cases vs. controls did not differ statistically. The proportion of GSTM1 null genotype in patients was 63% compared to 45% in controls group (OR = 2.03; 95% CI 0.97-4.24; p = 0.04). A significantly higher incidence of GSTM1 deletion genotype was found in smokers with bladder cancer compared to the controls (65.38% vs. 45.5%). Smokers lacking the GSTM1 gene are at an approximately 2.2-fold higher risk of bladder cancer (OR= 2.23, 95% CI 1-5.15; p = 0.03). CONCLUSION: This study suggests that in Tunisian subjects the GSTM1 null genotype may be associated with an increased risk of bladder cancer. This association appears to depend upon smoking status.     

The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population

Background: Susceptibility to bladder cancer is thought to depend on interplay between genetic factors and environmental chemical carcinogens.

Aim: This study seeks to determine the role of the glutathione transferases M1 and T1 null genotypes (GSTM1*0 and GSTT1*0) in individual susceptibility to bladder cancer in a Tunisian population.

Method: Sixty-two patients with transitional cell carcinoma of the bladder cancer and 79 controls were examined with respect to the frequency of GSTM1 and GSTT1 null genotypes.

Results: The frequencies of the GSTT1 null in the total group of bladder cancer cases vs. controls did not differ statistically. The proportion of GSTM1 null genotype in patients was 63% compared to 45% in controls group (OR?=?2.03; 95% CI 0.97–4.24; p?=?0.04). A significantly higher incidence of GSTM1 deletion genotype was found in smokers with bladder cancer compared to the controls (65.38% vs. 45.5%). Smokers lacking the GSTM1 gene are at an approximately 2.2-fold higher risk of bladder cancer (OR?=?2.23, 95% CI 1–5.15; p?=?0.03).

Conclusion: This study suggests that in Tunisian subjects the GSTM1 null genotype may be associated with an increased risk of bladder cancer. This association appears to depend upon smoking status.     

GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis

The results of studies investigating the associations between GSTM1 and GSTT1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity (ADIH) risk exhibit much controversy. Therefore, a meta-analysis was performed in order to examine the associations between GST variants and ADIH risk. A total of 451 relevant studies were identified through the digital medical databases Medline, Embase, and CBM published up to October 2012. Thirteen individual case–control studies were eventually recruited for GSTM1 null polymorphism (including 951 ADIH cases, 1,922 controls) and 12 studies for GSTT1 null polymorphism (847 cases, 1,811 controls). Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were appropriately calculated from fixed-effects or random-effects models. Subgroup analyses were stratified by ethnicity and different treatment combinations. The overall ORs of relevant studies that exhibited elevated ADIH risk was significantly associated with GSTM1 null genotypes (OR?=?1.36, 95 % CI 1.04–1.79), but for the GSTT1 polymorphism, no difference was found (OR?=?0.98, 95 % CI 0.82–1.18). In the subgroup analyses, the pooled results showed that GSTM1 null allele carriers had a significant association with ADIH risk in East Asians and the patients who used isoniazid (INH)?+?rifampicin (RMP)?+?pyrazinamide (PZA)?+?ethambutol (EMB), or?+?streptomycin (SM) (HRZES), but the opposite result was observed for patients using HR. Moreover, the GSTT1 null genotype evaluated the susceptibility to ADIH for tuberculosis using HRZ. This meta-analysis provides evidence that there may be an increased risk of ADIH in individuals with null genotypes of GSTM1 in the total population, especially East Asians and patients receiving HRZE or HRZES. However, polymorphisms of the GSTT1 null genotype seem to have no association with susceptibility to ADIH, except for patients receiving HRZ.     

Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss

The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.     

Glutathione S‐Transferase M1 and T1 Gene Polymorphisms and the Outcome of Chronic Hepatitis C Virus Infection in Egyptian Patients

We analysed the distribution of GSTM1 and GSTT1 gene polymorphisms in Egyptian patients with chronic hepatitis C, and investigated their relationship to the clinical outcome of chronic hepatitis C virus (HCV) infection. This study included 169 patients with chronic HCV infection and 145 healthy and matched controls.GSTM1 and GSTT1 polymorphisms were genotyped by multiplex polymerase chain reaction. Individual GSTM1 null and GSTT1 null genotypes were more frequent in patients versus control subjects [OR, 4 (95% CI, 2.5–6.4); P ? 0.001] and [OR, 1.7 (95% CI, 1.1–2.6); P = 0.025], respectively. The patient group showed a higher frequency of the combined GSTM1/GSTT1 double‐null genotype than the control group [OR, 1.8 (95% CI, 1.1–2.9); P = 0.016]. The distribution frequencies of the combined GSTM1/GSTT1 double‐null genotype were significantly different [OR, 0.5 (95% CI, 0.25–0.99); P = 0.049] between F0–F3 and F4. There were no significant differences between the two groups with regard to other genotypes. The combined GSTM1/GSTT1 double‐null genotype was significantly increased in Child‐Pugh C patients in comparison to Child‐Pugh A+B (P = 0.02). There was no significant difference between different classes with regard to other genotypes. In conclusion, we identified an association between the combined GSTM1/GSTT1 double‐null genotype and advanced liver fibrosis and outcome of chronic HCV infection in Egyptian patients.     

Impact of glutathione S-transferase M1 and T1 gene polymorphisms on the smoking-related coronary artery disease

Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogen generated by smoking. To analyze the effect of GSTM1/T1 gene polymorphisms on the development of smoking-related coronary artery disease (CAD), 775 Korean patients who underwent coronary angiography were enrolled. The subjects were classified by luminal diameter stenosis into group A (>50%), B (20-50%), or C (<20%). GSTM1 and GSTT1 gene polymorphisms were analyzed using multiplex polymerase chain reaction (PCR) for GSTM1/T1 genes and CYP1A1 gene for internal control. Of 775 subjects, 403 patients belonged to group A. They had higher risk factors for CAD than group B (N=260) and group C (N=112). The genotype frequencies of null GSTM1 and GSTT1 showed no significant differences among 3 groups. Considering the effect of GSTM1 gene polymorphisms on the smoking-related CAD, smokers with GSTM1 null genotype had more increased risk for CAD than non-smoker with GSTM1 positive genotype (odds ratios [OR], 2.07, confidence interval [CI], 1.06-4.07). Also the effect of GSTT1 gene polymorphism on smoking-related CAD showed the same tendency as GSTM1 gene (OR, 2.00, CI, 1.05-3.84). This effect of GSTM1/T1 null genotype on smoking-related CAD was augmented when both gene polymorphisms were considered simultaneously (OR, 2.76, CI, 1.17-6.52). We concluded that GSTM1/T1 null genotype contributed to the pathogenesis of smoking-related CAD to some degree.     

Glutathione S-transferase T1 status and gastric cancer risk: a meta-analysis of the literature

To clarify the risk of gastric cancer associated with glutathione S-transferase T1 (GSTT1) status, a meta-analysis of published studies was performed. Eligible studies included all reports investigating an association between GSTT1 status and gastric cancer published before October 31, 2005. A qualitative scoring of papers was applied to evaluate the quality of the published data. The principal outcome measure was the odds ratio (OR) for the risk of gastric cancer associated with GSTT1 deletion status using a random effects model. Eighteen case-control studies detailing a possible association between the GSTT1 null genotype and gastric cancer were selected. Combining data from these studies, totalling 2508 cases and 4634 controls, a non-statistically significant OR for gastric cancer risk associated with GSTT1 deficiency emerged [OR = 1.09; 95% confidence interval (CI): 0.97-1.21; I(2) = 0%]. When only high-quality scored studies were considered, a statistically significant increased risk appeared (OR = 1.23; 95% CI: 1.04-1.45; I(2) = 0%), as well as considering only Caucasians (OR = 1.23; 95% CI: 1.03-1.56; I(2) = 0%). By pooling data from seven studies (319 cases and 656 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for gastric cancer (OR = 1.95, 95% CI: 1.42-2.67; I(2) = 0%) was detected for individuals with deletion mutations in both genes compared with wild-types. In conclusion, this meta-analysis suggests that the GSTT1 null genotype may slightly increase the risk of gastric cancer and that interaction between unfavourable GST genotypes may exist. Greater attention should, therefore, be paid to the design of future studies; the investigation of interactions among multiple genotypes and environmental exposures are justified to clarify GSTT1 null status influence on gastric cancer risk.     

Glutathione S-transferase Mu null genotype affords protection against alcohol induced chronic pancreatitis

Glutathione S-transferases (GSTs) play critical roles in providing protection against electrophiles and products of oxidative stress, by catalysing the formation of glutathione conjugates and by eliminating peroxides. Most extensively studied are four main families of human cytosolic GST: GSTAlpha(A), GSTMu(M), GSTPi(P) and GSTTheta(T). Absence of GSTM1 or GSTT1 can be attributed to absence of the GSTM1 or GSTT1 gene products (null genotype) in approximately 50% and 20% of the Caucasian population, respectively. We investigated whether polymorphisms in the GSTM1, GSTT1 and GSTP1 genes modified the risk for chronic pancreatitis (CP). DNA samples were obtained from 142 adult CP patients with alcoholic (n = 79), hereditary (n = 21) or idiopathic (n = 42) origin. DNA from 204 healthy controls and from 57 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in GSTs were determined by PCR, eventually followed by restriction-fragment-length-polymorphism analyses in all subjects. The rates of GSTT1 and GSTP1 genotypes did not differ between CP patients and healthy controls. However, GSTM1 null genotypes were significantly less common in alcoholic CP patients (OR = 0.56, 95% CI: 0.33-0.95) as compared to healthy controls and to alcoholic controls (OR = 0.52, 95% CI: 0.26-1.04). Age- and sex-adjustment bolstered our finding (adjusted OR = 0.48, 95% CI: 0.26-0.89). The frequency of the GSTM1 null genotype is significantly lower in alcoholic CP patients, especially young female. This suggests that GSTM1 null alcohol users, particularly young female, are less susceptible to CP.     

Relationship between glutathione S-transferase gene polymorphisms and enzyme activity in Hong Kong Chinese asthmatics

BACKGROUND: Asthma is a disease associated with oxidative stress. The glutathione S-transferases (GST) are a group of enzymes that protect cells from oxidative stress. Functional genetic polymorphisms of GST genes (GSTT1, GSTM1 and GSTP1) have previously been reported. OBJECTIVE: To investigate the association of GST gene polymorphisms and its enzyme activity with the risk of asthma in Hong Kong Chinese adults. METHODS: An age- and smoking status-matched case-control study was carried out on 315 patients with asthma and 315 healthy controls. Genotyping was carried out on genomic DNA using the PCR and/or restriction fragment length polymorphism (PCR-RFLP). Plasma GST activity was measured by fluorometric assay. RESULTS: The distribution of various genotypes or alleles of the GSTT1, GSTM1 and GSTP1 was not significantly different between patients with asthma and healthy controls. The GSTM1 null genotype was found to be protective from the development of asthma in atopic subjects (odds ratios 0.55, 95% confidence interval 0.34-0.90; P=0.017). However, there was no association between GSTT1 and GSTM1 null genotypes and enzyme activity. GSTP1 codon 105 Val variants led to reduced plasma GST activity in healthy controls. Asthma patients had elevated plasma GST activity compared with healthy controls irrespective of their genotypes (P<0.001). CONCLUSION: Our data suggest that among atopic subjects, the GSTM1 null genotype is associated with a decreased risk for asthma despite increased level of plasma GST activity in asthma, but it could not distinguish whether this increase is a potentially protective compensatory effect or a pathogenic factor.     

Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population

BACKGROUND: We investigated the relationship between idiopathic recurrent pregnancy loss (RPL) and genetic polymorphisms in phase I and phase II detoxification genes which include CYP1A1, CYP2D6, GSTM1, GSTP1 and GSTT1. METHOD: A case-control study comprised 160 females with RPL and 63 healthy controls with a successful reproductive history. RESULTS: The CYP1A1 variant allele was present at frequencies of 0.61 and 0.44 in cases and controls, respectively (odds ratio=1.93; P=0.023, 95% confidence interval 1.10-3.38). The CYP2D6 variant allele was present at a frequency of 0.17 in females with RPL, while in the control population the frequency was 0.16. The GSTM1 and GSTT1 null genotypes were present at frequencies of 0.39 and 0.26 in RPL cases, whereas in controls the frequencies were 0.37 and 0.17, respectively. The mutant GSTP1 frequencies in case and control women were 0.38 and 0.40, respectively. We report a significant association of the CYP1A1*2A allele with RPL which is confirmed by logistic regression analysis. No association was observed for the other polymorphisms or in their combinations studied. CONCLUSIONS: The present study suggests the occurrence of the CYP1A1*2A allele as a probable risk factor in idiopathic recurrent miscarriages.     

GSTM1, GSTT1 and GSTP1 polymorphisms in the Korean population

The isoenzymes of the glutathione s transferase (GST) family play a vital role in phase II of biotransformation of many substances. Using a multiplex polymerase chain reaction and a direct sequencing analysis, the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated in 1,051 Korean male subjects. We found that 53.8% of the individuals had the GSTM1 null genotype and 54.3% had the GSTT 1 null genotype. The genotypic distribution of GSTP1 was Ile105/Ile105 in 68.4%, Ile105/Val105 in 29.1% and Val105/Va105 in 2.5%. The most frequently observed combination of GSTM1, GSTP1 and GSTT1 genotypes was Null type/Ile105/Ile105/Null type, while the combination of Non-null type/Val105/Val105/Non-Null type was not observed. We found that the genotype distributions of three GST isoenzymes in the Koreans are similar to those reported in Asians and previously reported Koreans. We believe our results, which are represented by a large population, are reliable estimates of the frequencies of the polymorphic GST alleles in the Koreans and will help future researches on GST polymorphisms.     

Genetic polymorphisms of CYP2D6, GSTM1, and GSTT1 genes and bladder cancer risk in North India

The study consisted of 100 patients (97 males and 3 females) suffering from bladder cancer and 76 matching controls. The maximum number of patients in this study was in the age group of 61-70 years. The prevalence of genetic polymorphism in the CYP2D6, GSTM1, and GSTT1 genes has been investigated to find their association with risk of bladder cancer. While there was no association between the heterozygous (HEM) genotype of the CYP2D6 gene with the risk of bladder cancer [odds ratio (OR)=1.00; 95% confidence interval (CI)=0.46-2.16], it was 1.5-fold with poor metabolizers (PM) genotype. When stratified according to different grades of bladder cancer, a significant association was found with an OR=3.54 (95% CI=0.89-13.98) in grade II, 3.3 (95% CI=0.12-20.6) in grade III, and 1.67 (95% CI=0.15-18.45) in grade IV. When stratified in relation to smoking status, significant association of the disease was found in heavy smokers with an OR=2.13 (95% CI=0.71-6.43). Subjects with the null genotype for GSTM1 had a slightly significant association with the bladder cancer risk and the risk increased to 2-fold with the GSTT1 null genotype. Smoking status also revealed an impact on the prevalence of bladder cancer in the individuals with GSTM1 and GSTT1 null genotypes. The results indicated that there is a 3-fold increase in risk of developing this cancer in the presence of one copy of the variant CYP2D6 (HEM) allele and null GSTT1.     

Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.     

Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk-modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1-6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk-elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0-111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL.     

Genetic and environmental interactions on oral cancer in Southern Thailand

Many countries are interested in understanding the relationship between genetic susceptibility and their prevalent environmental cancers for disease prevention. In Thailand we conducted a population-based case-control study of 53 matched pairs to assess the risk of oral cancer in relation to genetic polymorphism of the glutathione-S-transferase genes (GSTM1 and GSTT1) in cigarette smokers, alcohol drinkers, and betel quid chewers. Interaction of the genes with other potential risk factors such as local bean consumption were also elucidated. Homozygous deletion of GSTM1 has a frequency of 56.6% (n = 30 over 53) among the patients and 30.2% (16/53) among the controls. This gene is associated with a 2.6-fold higher risk for development of oral cancer (95% CI 1.04-6.5). Among the null GSTM1 individuals, those who smoke, consume alcohol, and/or chew betel quid have a significantly increased risk for oral cancer with an odd ratio (OR) = 4.0 (95% CI = 1.2-13.7), OR = 7.2 (95% CI = 1.5-33.8), and OR = 4.4 (95% CI = 1.1-17.8), respectively. Interactions between any two of the lifestyle habits for oral cancer risk, however, are not found. The frequency of the GSTT1 null genotype is 34.0% (18/53) among the patients and 47.2% (25/53) among our controls. There is no association between the GSTT1 null allele and oral cancer risk. In conclusion, our study provides data to indicate that individuals who have homozygous deletion of the GSTM1 gene have increased risk for oral cancer. The risk increases further when these individuals are exposed to environmental toxicants such as chemicals in cigarette smoke, alcohol, and betel quid. These baseline data can be applied to a larger population-based study, both to verify the observation and to conduct mechanistic investigations.